Tompkins Nathan, Spinelli Kateri J, Choi Dongseok, Barr-Gillespie Peter G
Oregon Hearing Research Center and Vollum Institute, Oregon Health and Science University, Portland, Oregon.
School of Public Health, Oregon Health and Science University, Portland, Oregon; Graduate School of Dentistry, Kyung Hee University, Seoul, South Korea.
Biophys J. 2017 Oct 17;113(8):1868-1881. doi: 10.1016/j.bpj.2017.08.029.
Tip links are thought to gate the mechanically sensitive transduction channels of hair cells, but how they form during development and regeneration remains mysterious. In particular, it is unclear how tip links are strung between stereocilia so that they are oriented parallel to a single axis; why their polarity is uniform despite their constituent molecules' intrinsic asymmetry; and why only a single tip link is present at each tip-link position. We present here a series of simple rules that reasonably explain why these phenomena occur. In particular, our model relies on each of the two ends of the tip link having distinct Ca-dependent stability and being connected to different motor complexes. A simulation employing these rules allowed us to explore the parameter space for the model, demonstrating the importance of the feedback between transduction channels and angled links, links that are 60° off-axis with respect to mature tip links. We tested this key aspect of the model by examining angled links in chick cochlea hair cells. As implied by the assumptions used to generate the model, we found that angled links were stabilized if there was no tip link at the tip of the upper stereocilium, and appeared when transduction channels were blocked. The model thus plausibly explains how tip-link formation and pruning can occur.
纤毛顶端连接被认为是毛细胞机械敏感转导通道的闸门，但它们在发育和再生过程中如何形成仍然是个谜。特别是，目前尚不清楚纤毛顶端连接是如何在静纤毛之间串联起来，从而使其平行于单一轴定向；尽管其组成分子具有内在不对称性，但其极性为何是均匀的；以及为什么在每个纤毛顶端连接位置只存在一个纤毛顶端连接。我们在此提出了一系列简单规则，合理地解释了这些现象为何会发生。特别是，我们的模型依赖于纤毛顶端连接的两端具有不同的钙依赖性稳定性，并连接到不同的运动复合体。利用这些规则进行的模拟使我们能够探索该模型的参数空间，证明了转导通道与倾斜连接（相对于成熟纤毛顶端连接偏离轴60°的连接）之间反馈的重要性。我们通过检查鸡耳蜗毛细胞中的倾斜连接来测试该模型的这一关键方面。正如用于生成该模型的假设所暗示的，我们发现如果上部静纤毛顶端没有纤毛顶端连接，倾斜连接会稳定下来，并且在转导通道被阻断时出现。因此，该模型合理地解释了纤毛顶端连接的形成和修剪是如何发生的。
